Dr. Lang's overall goal is to transition from a quantitative focus in engineering and quantitative genetics to a more biologically oriented focus in molecular genetics and bioinformatics. The candidate's long term career objective is to function independently as a principle investigator with a research emphasis in skeletal molecular genetics, with specific interest in the response of the skeleton to mechanical loading and exercise. This career development award will provide training and experience in molecular biology, molecular genetics, bioinformatics and musculoskeletal aging that will enhance the applicant's existing skills in engineering, biomechanics, and quantitative genetics and enable the candidate to successfully compete for independent funding in the biosciences. The principal investigator's main objectives are to develop the knowledge, skills and experience required to perform gene expression analyses and bioinformatics techniques on brain, muscle, and skeletal tissue, and gain research experience measuring activity level and implementing exercise intervention in mice. The study will expose C57BL/6J (B6)and DBA/2J (D2)inbred strains to treadmill exercise during young and old age. An over-riding theme is to integrate findings from ongoing studies using quantitative genetics with findings from the proposed molecular genetics work. Our specific aims include the following for each B6 and D2 strain: 1) Expose mice to daily doses of treadmill exercise 2) Measure physical activity level 3) Determine muscles mass 4) Determine the architecture, composition, and mechanical performance of femora, tibiae, and vertebrae 5) Perform dynamic histomorphometry 6) Determine differential gene expression within bone, muscle, and brain tissue as a function of age, exercise, and genetic strain 7) Integrate gene expression and pre-existing QTL mapping data to identify candidate genes that exhibit both quantitative effects on bone quality and molecular changes in gene expression. 8) Subject candidate genes to Real Time-PCR to quantify and confirm mRNA levels. The broad goal is to better understand the relationship of age-related bone loss to changes in daily activity, muscle mass, and exercise over the lifespan. Identifying genotype by environmental interactions by investigating the differential response of two inbred mouse strains to treadmill exercise could lead to a better understanding of the impact of exercise intervention relative to genetic predisposition.